AMIS syndrome describes a cluster of related pathologies that include obesity, diabetes, cardiovascular disease, retinal and kidney failure, and the metabolic dysfunctions associated with the originally-named Syndrome X. The original name of the syndrome and the subsequent 13 attempts to rename it, including the American Diabetes Association's renaming as Cardiometabolic Risk (CMR) (Grundy et al., 2005), did not determine a mechanistic link between the pathologies, other than as risk factors for other of the pathologies.
The suggestion to refer to this cluster of pathologies as the AMIS syndrome is based on the discovery of the phenomenon and mechanism of Meal-induced Insulin Sensitization (MIS), and how Absence of Meal-induced Insulin Sensitization (AMIS) results in the initiation of a progressive, predictable cluster of pathologies that are not diagnosed until well into the AMIS syndrome.
MIS is demonstrated by a much larger hypoglycemic response to insulin after a meal as compared with the response to insulin in the fasted state, as first reported in 2001 by the present inventor in rats (Lautt et al., 2001) and later confirmed by the present inventor in humans (Patarrao et al., 2008).
The degree of MIS is determined by the ability of pulses of insulin to cause the secretion of Hepatic Insulin Sensitizing Substance (HISS) from the liver. HISS is released from the liver in response to pulses of insulin, but only in the presence of 2 synergistic, permissive feeding signals, one neural via the hepatic parasympathetic nerves and one chemical through elevation of hepatic glutathione levels (Lautt et al., 2011). The nerve response is mediated by nitric oxide and cGMP. The feeding signals are activated by the presence of food in the upper GI tract, even if the food is a liquid injected into the stomach of anesthetized rats (Sadri et al., 2006). This knowledge of the biological role and signaling pathway of HISS is based on studies by the present inventor.
HISS more than doubles the hypoglycemic effect of insulin in rats (Lautt et al., 2001), and triples the effect in humans (Patarrao et al., 2008). The proportion of nutrient energy stored as glycogen or lipids is dependent on the balance between HISS and insulin. HISS acts by selective stimulation of glucose uptake and storage as glycogen in skeletal muscle, heart and kidneys, but not the liver, adipose tissue, or pancreas (Fernandez et al., 2011).
AMIS results in a reduction of at least 50% of the hypoglycemic response to secreted insulin for a single meal. AMIS occurs in states of stress (Seredycz et al., 2006). AMIS is induced by an isocaloric sucrose supplemented diet (Ribeiro et al., 2005), a high fat diet (Afonso et al., 2010), or fetal exposure to maternal consumption of alcohol (Sadri et al., 2003). AMIS occurs progressively with age (Lautt et al., 2008).
Glucose levels are well maintained despite AMIS, as long as increased insulin secretion can compensate for lack of HISS action. Increased insulin secretion almost fully compensates the resulting mild hyperglycemia after about 2 hours. Insulin, however, stimulates adipocytes and hepatocytes to form lipids for peripheral fat storage. The result is that in AMIS, where increased insulin secretion is necessary to compensate for lack of HISS action, nutrient storage after a meal shifts from glycogen to lipids. AMIS accounts for postprandial hyperglycemia, hyperinsulinemia and hyperlipidemia.
Alternatively, hyperglycemia can be controlled via the administration of insulin or cellular insulin sensitizers. However, this treatment is associated with adiposity since, as described above, insulin stimulates adipocytes and hepatocytes to form lipids for peripheral fat storage.
Direct insulin action is not altered by feeding (Sadri et al., 2006) so that the increased response to a bolus of insulin is not sensitized at the cellular level but rather at the whole body homeostatic level. Based on the in vivo bioassay procedure, invented by the present inventor in 1996 and used for cats and rats, and later for humans (Lautt et al., 2001), the biological activity of HISS has been well studied, and the pathologies of syndrome X have been shown to be strongly related to lack of HISS action, in the absence of altered direct insulin sensitivity (Xie et al., 2006).
AMIS is prevented and reversed in diabetic rats by voluntary exercise (Chowdhury et al., 2011). The present inventors developed a therapeutic that restores the response to each meal when the 2 feeding signals are mimicked (Lautt et al., 2011) and a targeted synergistic antioxidant cocktail that prevents or strongly inhibits the long term effects of a high sugar diet and aging (Lautt et al., 2010) by preservation of the ability of insulin to cause secretion of HISS.
The identification of the HISS compound is a novel discovery. Though two groups have previously claimed to identify HISS, neither identification was correct. A Hungarian team claimed that Somatostatin was HISS (Porszasz et al., 2003), however, somatostatin is actually a very effective blocker of HISS release and has no hypoglycemic action (Seredycz et al., 2006). A Brazilian team claimed that bone morphogenetic protein 9 was HISS (Caperuto et al., 2008), but the molecule has no rapid hypoglycemic effect and only acts after several hours. HISS, in contrast, is metabolized as quickly as insulin.